Respiratory syncytial virus (RSV) is a major respiratory pathogen in infants, young children, and the elderly, causing severe bronchiolitis, pneumonia, and exacerbation of asthma. In the United States alone, RSV causes approximately 4 million cases of respiratory tract infection annually, which results in 149,000 hospitalizations and 11,000 deaths. It has been established that interferon-gamma (IFN-γ) gene therapy is effective against RSV infection in BALB/c mice (Kumar et al., Vaccine 18, 558-567, 1999).
Intranasal administration of a plasmid expressing IFN-γ cDNA proved to be an effective prophylaxis in mice. Furthermore, IFN-γ expressed by a recombinant respiratory syncytial virus attenuates virus replication in mice without compromising immunogenicity. IFN-γ, a type II interferon, is a pleotropic cytokine which plays an important role in modulating nearly all phases of immune and inflammatory responses. IFNs bind to specific receptors on cells and activate the JAK-STAT signaling cascade, which culminates in the transcriptional induction of IFN-stimulated genes (ISGs). The Jak1 and Jak2 phosphorylate STAT-1 following the binding of IFN-γ to its receptor. Once phosphorylated, STAT molecules dimerize and translocate to the nucleus and bind to gamma activated sequence (GAS) elements present in the regulatory regions of various ISGs. The antiviral mechanism of IFN-γ may involve one or more of a number of ISG-encoded products, including interferon regulatory factor-1 (IRF-1) double stranded RNA-dependent protein kinase (PKR), the Mx family of proteins, a family of 2′-5′-oligoadenylate synthetases (2-5 AS), and RNase L.
RNase L is constitutively expressed in most mammalian cells and is found in an inactive form bound to RNase L inhibitor (RLI), a 68 kDa protein not regulated by IFN-γ. The 2-5 AS produces a series of 5′ phosphorylated, 2′, and 5′-linked oligoadenylates (2-5A) from ATP, when activated by double-stranded ribonucleic acid (dsRNA). Upon binding of 2-5 AS with RNase L, RLI is released and consequently, RNase L is dimerized and activated, mediating the cleavage of single-stranded RNA. However, the mechanism of the induction and activation of each of these genes is different in different cells and for the types of viruses. The mechanism of the IFN-γ-mediated anti-viral activity remains to be elucidated for many clinically important viruses.